Immunotherapy strategies involving antibody-induced signaling through antigen-specific T-cell receptors (TCR) have been shown to ameliorate autoimmune and inflammatory diseases, likely by regulating the immune response to self-antigens. CD3 (Cluster of Differentiation 3) is an example of such a receptor. Injected anti-CD3 monoclonal antibody (mAb) therapy in particular has been shown to be efficacious in preventing and reversing the onset of diabetes in NOD mice (Belghith et al, Nat Med 9: 1202-8, 2003) and in treating subjects with Type 1 diabetes (Herold et al, N Engl J Med 346: 1692-82, 2002). Anti-CD3 antibodies also reverse experimental allergic encephalomyelitis (EAE) in Lewis rats with a suppressive effect on T-helper type 1 (Th1) mediated immunity (Tran et al, Intl Immunol 13: 1109-20, 2001). Orthoclone OKT3™ (muromonab-CD3; Ortho Biotech Products, Bridgewater, N.J.) is a murine anti-CD3 IgG2a mAb, approved for intravenous injection for the treatment of graft rejection after transplantation (Chatenoud, Nat Rev Immunol 3: 123-32, 2003). After injection of Orthoclone OKT3™, CD3+ T cells are removed from circulation, what has been effective in reversing corticosteroid-resistant acute graft rejection in renal, liver, and cardiac transplant recipients. Humanized mAbs specific to CD3 were developed, also having reduced binding to the Fcγ receptors. These humanized antibodies include otelixizumab, teplizumab, and visilizumab.
U.S. Pat. No. 7,883,703 (Weiner et al) discloses that anti-CD3 antibodies are also useful for the treatment of autoimmune diseases when administered orally or mucosally. The success of such oral or mucosal administration involves activation of regulatory T cells (Tregs) in the mucosal immune system, which in turn leads to an amelioration or down-regulation of the undesired immune system effects, hence ameliorating or at least reducing the pathology of autoimmune and inflammatory diseases. Among the advantages of the oral or mucosal route over the systemic route of administration of anti-CD3 mAb is the ability to avoid the serious adverse events (AEs) and generalized immune-suppression associated with systemic administration of anti-CD3 mAb.